Page 88 - 2018_12-Haematologica-web

L.G. Riley et al.
A
BC
Figure 1. Representation of mutated YARS2 proteins. (A) Schematic view of YARS2 domains: MTS: mitochondrial targeting sequence; ACB: anticodon binding domain; S4-Like: S4 ribosomal protein-like domain. Amongst all the variants identified, only those tested in this study are shown in cyan. Note that the recombinant YARS2 used in the amino-acylation assays is deprived of the MTS. (B) Model of YARS2 p.(Thr197-Leu208del), built with I-TASSER.28 The structural domains from (A) are shown with the same color code. The locations of the variants, which have the weakest effects on amino-acylation [p.(Leu61Val), p.(Met195Ile), p.(Tyr236Cys)] are shown in cyan. (C) Crystal structure of YARS2 catalytic domain19 with the tyrosyl-adenylate analog (TyrAMS, magenta) bound to the active site. The locations of variants p.(Ser203Ile) and p.(Gly244Ala), characterized by the strongest effects on amino-acylation, are indicated in cyan.
Table 2. In silico predictions of pathogenicity for YARS2 missense variants.
YARS2 SIFT SIFT variant prediction score
p.(Leu61Val) Deleterious 0.03
p.(Met195Ile) Tolerated 0.17
p.(Ser203Ile) Deleterious 0.02
p.(Tyr236Cys) Tolerated 0.09
p.(Gly244Ala) Deleterious 0.00
*No homozygotes reported.
moderate myopathy (P7). Patient 1 (P1) with severe lactic acidosis and myopathy had combined respiratory chain deficiency in skeletal muscle, and the muscle biopsy showed histopathological features typical of a mitochon- drial myopathy, including ragged red fibers on trichrome stain and “parking lot” inclusions and whorled arrays of mitochondrial cristae by transmission electron microscopy (data not shown). In one family, the proband (P9a) and his clinically unaffected, but genotypically iden- tical sibling (P9b), had distinctive “triangular” faces, unlike their parents or genotypically normal sibling, which has not previously been reported in association with YARS2 variants, but has been described in mitochondrial myopa- thy with lactic acidosis and sideroblastic anemia 1 (MLASA1; OMIM #600462) due to pseudouridine syn- thase 1 (PUS1) variants.17
PolyPhen2 prediction
Benign
Possibly damaging Probably damaging Probably damaging Probably damaging
PolyPhen2 score
0.001
0.827 0.989 1.000 0.995
gnomAD frequency (%)
0.0016*
0
0 0.0008* 0.0047*
YARS2 variants in patients with congenital sideroblastic anemia
We identified three previously described YARS2 variants and ten novel variants in patients with CSA: the Lebanese Christian founder variant, p.(Phe52Leu),4 was in the homozygous state in 4 patients; the p.(Asp311Glu) variant8 homozygous in one patient; and a novel variant, p.(Leu61Val) homozygous in one patient. The remaining six families had compound heterozygous variants including four novel missense variants: p.(Met195Ile), p.(Ser203Ile), p.(Tyr236Cys), p.(Gly244Ala); a novel nonsense variant p.(Ser33*); three novel indels, p.(Thr197_Leu208del), p.(Leu389Cysfs*6), p.(Ile454Serfs*10); one novel splicing variant, c.1104-1G>A; and two previously reported mis- sense variants, p.(Gly191Val) and p.(Asp311Glu).5,8 No patient had two indel or splicing variants.
2012
haematologica | 2018; 103(12)